Lipase inhibitors have been used in the prevention or treatment of obesity and hyperlipaemia by inhibiting the activity of lipase which hydrolyzes triglyceride to form glycerol and free fatty acid, thereby reducing fat absorption into the body. Such lipase inhibitors include lipstatin, orlistat, panclicins, hesperidin, ebelactones, esterastin and derivatives thereof, and valilactone, among these, orlistat known as tetrahydrolipstatin is derived from natural substance excreted by Streptomyces toxytricini. Orlistat is a strong inhibitor of various lipase including gastric lipase, pancreatic lipase and carboxyl ester lipase, and its use for the control or prevention of obesity and hyperlipidaemia is described in U.S. Pat. No. 4,598,089, and it is sold under the trademark XENICAL® to be administered in 120 mg dose per meal to inhibit fat uptake by about 30%.
The unabsorbed fat by the action of the lipase inhibitor, however, reduces water absorption in the colon, and it forms a separated oil component in the stool, inducing such side effects as oily spotting, abdominal distension, flatus, fecal urgency, fatty/oily stool, increased defecation and fecal incontinence which lead to patients' difficulties and incompliance on lipase inhibitor dosage (See Mark Fox et al., Diseases of the Colon & Rectum, 47, 2147-2156, 2004). Accordingly, many attempts have been made to reduce such side effects.
Oily spotting, in particular, has been occasionally observed in the stool of patients treated with lipase inhibitors, and many studies have been conducted to solve such side effects through the use of surfactants, emulsifiers or dispersants for dispersing unabsorbed fat in the colon, or through the use of high-viscous substances such as dietary fiber for increasing the viscosity of water in the colon, which is effective in the prevention of oil emulsion coalescence. Also, the physical adsorption of oil with a lipophilic compound has been studied.
For example, International Patent Publication WO 2000/09122 discloses that the oil emulsion coalescence can be minimized when an emulsifier such as Ryoto Sugar Ester is used in mixing or dispersing water and oil and combining the resulting mixture with a hydrophilic hydro colloidal thickener. However, such an emulsifier addition can increase fat absorption in the upper colon, and the thickener is not sufficiently effective in adsorbing free oil.
International Patent Publication WO 2001/19340 discloses that the oil leakage phenomenon can be reduced by solubilizing orlistat with a surfactant and at least one dispersant, to improve lipase inhibition and free oil dispersion. However, the solubilized orlistat tends to be absorbed into the blood through the gastrointestinal (GI) tract, which may induce unexpected adverse effects.
International Patent Publication WO 2002/98412 discloses that the side effects of unabsorbed fat can be reduced by using sucrose fatty acid ester surfactant to increase the orlistat activity in the GI and to convert free oil into a stable emulsion in the colon. However, the formation of a stable emulsion in the GI tract by the addition of a surfactant is difficult to achieve because of the unsteady environment of the GI tract, also it requires an appropriate pharmaceutical mean for the surfactant to function as an enhancer of orlistat in the small GI as well as an emulsifier in the colon.
Furthermore, International Patent Publication WO 2003/090742 discloses that the oil emulsion coalescence can be prevented by using konjac (glucomannan) together with a lipase inhibitor to increase water viscosity in the colon and stabilize unabsorbed oil. This is, however, possible only in vitro experiment conditions having a limited moisture content, but not in the colon which undergoes frequent water absorption.
Also, International Patent Application WO 2000/09123 discloses the reduction of oil leakage by the use of chatoyant for adsorbing free fat, but it is reported that such an effect can not be achieved in a clinical experiment (See M. D. Gades and J. S. Stern, International Journal of Obesity, 26, 119-122, 2002; and Roberto Guerciolini et al., Obesity Research, 9(6): 364-367, 2001).
Accordingly, the present inventors have endeavored to reduce side effects caused by a lipase inhibitor and found that a lipophilic oil absorbent having a low density in the solid state can adsorb unabsorbed oil and increase the viscosity thereof, thereby minimizing the side effects.